Non-liver-related mortality in the DAA era: Insights from post-SVR patients with and without previous HCC history.

BACKGROUND AND AIMS: Mortality after sustained virological response (SVR) with interferon-free direct-acting antiviral (IFN-free DAA) therapy is crucial for optimizing post-SVR patient care, but it remains unclear, especially regarding non-liver-related mortality. METHODS: Consecutive post-SVR patients from 14 institutions were stratified into three cohorts: A (without advanced fibrosis and without prior HCC), B (with advanced fibrosis and without prior HCC), and C (curative HCC treatment). We assessed mortality (per 1000 person-years [/1000PY]) post-SVR. Mortality rates were compared between cohorts A and B and the general population using age- and sex-adjusted standardized mortality ratio (SMR). Comparison of survival between each cohort was performed using propensity-score (PS) matching with sex, age, and comorbidity. RESULTS: In cohort A (n = 762; median age, 65 years), 22 patients died (median follow-up, 36 months); all-cause mortality was 10.0/1000PY, with 86.4% non-liver-related deaths. In cohort B (n = 519; median age, 73 years), 27 patients died (median follow-up, 39 months); all-cause mortality was 16.7/1000PY, with 88.9% non-liver-related deaths. In both cohorts, malignant neoplasm was the most common cause of death; all-cause mortality was comparable to that of the general population (SMR: 0.96 and 0.92). In cohort C (n = 108; median age, 75 years), 15 patients died (median follow-up, 51 months); all-cause mortality was 36.0/1000PY, with 53.3% liver-related deaths. PS matching showed no significant survival differences between cohorts A and B, both of which had better survival than cohort C. CONCLUSIONS: Mortality varies based on HCC history in the DAA era; nevertheless, attention should be paid to non-liver-related deaths in all post-SVR patients.

Liver Function in Older Patients With Unresectable Hepatocellular Carcinoma After Administration of Lenvatinib.

BACKGROUND: The age of patients with advanced hepatocellular carcinoma (HCC) eligible for molecular-targeted drug treatment is increasing. We assessed liver function after lenvatinib administration according to age in patients with advanced HCC. PATIENTS AND METHODS: In this retrospective, multicenter, observational study, we reviewed the records of patients with HCC who received lenvatinib treatment (March 2018-March 2020). Liver function was measured using the Albumin-Bilirubin Index (ALBI). RESULTS: Of 119 patients, with a median age of 72.0 years, median overall survival was 15.3 months. Overall survival was significantly better in the group which maintained liver function (p=0.02). Older age (≥72 years) was associated with liver-function deterioration within 8 weeks (odds ratio=2.47, 95% confidence interval=1.06-5.75, p=0.035). The ALBI score was significantly higher in the older group at 4 and 8 weeks after lenvatinib administration. CONCLUSION: Lenvatinib administration was more likely to adversely affect liver function in older patients; dose adjustment should be considered in such patients.

Influence of Interferon-free Direct-acting Antiviral Therapy on Primary Hepatocellular Carcinoma Recurrence: A Landmark Time Analysis and Time-dependent Extended Cox Proportional Hazards Model Analysis.

Objective The influence of interferon (IFN)-free direct-acting antiviral (DAA) on hepatocellular carcinoma (HCC) recurrence remains unclear. Previous retrospective analyses revealed that the time interval between HCC curative treatment and IFN-free DAA induction is the critical factor affecting HCC recurrence. Thus, this study aimed to examine the influence of DAA therapy on HCC recurrence considering this interval. Methods Factors contributing to HCC recurrence were retrospectively analyzed using a landmark time analysis and time-dependent extended Cox proportional hazards model. Patients After screening 620 patients who were diagnosed with primary HCC from January 2001 to December 2016, 76 patients with early-stage (primary and solitary) disease who received curative treatment and were positive for serum hepatitis C virus RNA were included. Results HCC recurrence was observed in 8 of 17 (47.1%) patients who had received IFN-free DAA therapy and 45 of 59 (76.3%) who had not. No significant difference was seen between the IFN-free DAA (-) and IFN-free DAA (+) groups in the landmark time and time-dependent Cox proportional hazards model analyses. However, IFN-free DAA therapy tended to decrease the HCC recurrence rate after curative treatment for primary HCC in patients with chronic hepatitis. In addition, IFN-free DAA therapy tended to decrease the second HCC recurrence rate after treatment for the first HCC recurrence. Conclusion Our results, with a consideration of the time interval between HCC curative treatment and IFN-free DAA induction, showed that IFN-free DAA therapy was not associated with early-stage HCC recurrence after curative treatment.

Extracellular vesicles from senescent hepatic stellate cells promote cell viability of hepatoma cells through increasing EGF secretion from differentiated THP-1 cells.

Since the discovery of the senescence-associated secretory phenotype, the role of senescent hepatic stellate cells (HSCs) in hepatocellular carcinoma (HCC) development has gained increasing attention. Similar to cytokines, extracellular vesicles (EVs) are essential for intercellular communication. However, the function of EVs derived from senescent HSCs in HCC progression has not been extensively studied. The aims of the present study were to characterize the EVs derived from senescent HSCs and determine their role in the tumor microenvironment. Cellular senescence was induced in human hepatic stellate cells (HHSteCs) with various concentrations of etoposide. Induction was confirmed using EdU staining and 53BP1 and p21 immunostaining. EVs were isolated by ultracentrifugation and analyzed by nanoparticle tracking analysis. Multiplex immunoassays were used to compare the levels of growth factors secreted from hepatoma cell lines and macrophage cells pretreated with EVs derived from senescent HHSteCs (senescent EVs) with those pretreated with EVs derived from normal cultured HHSteCs (normal EVs). Treatment with 25 µM etoposide for 3 days was the most effective at inducing senescence in HHSteCs. This finding was confirmed by induction of irreversible cell-cycle arrest, upregulation of 53BP1 and p21 expression, and increased SA-ß-gal staining. Senescent HHSteCs released increased quantities of EV particles compared with normally cultured HHSteCs. Multiplex analysis revealed that there was no difference between hepatoma cell lines treated with normal EVs and those treated with senescent EVs in growth factor secretion. In contrast, the secretion of epidermal growth factor (EGF) was increased by macrophage cells treated with senescent EVs compared with those treated with normal EVs. Furthermore, senescent EVs did not affect the viability of hepatoma cells but increased the viability of hepatoma cells co-cultured with macrophage cells. In conclusion, the release of EVs from senescent HSCs was higher compared with normal HSCs. Furthermore, senescent EVs promoted HCC development by upregulating EGF secretion from macrophages.

The Long-term Efficacy of Sodium Glucose Co-transporter 2 Inhibitor in Patients with Non-alcoholic Fatty Liver Disease.

Objective Sodium glucose co-transporter 2 inhibitor (SGLT-2i), recommended for patients with type 2 diabetes, has been reported to improve the liver function test results in non-alcoholic fatty liver disease (NAFLD). However, the long-term effects of SGLT-2i on the liver function and body weight in NAFLD patients have not been fully elucidated. In this study, we investigated the long-term effects of SGLT-2i in NAFLD patients. Methods Twenty-two diabetic patients with NAFLD were enrolled in this study. We assessed the body weight, liver enzyme levels, metabolism, and glucose levels at 12 months (22 cases) and 24 months (15 cases) after the initiation of SGLT-2i. The changes in controlled attenuation parameter (CAP) and liver stiffness in 20 of the 22 patients were evaluated using transient elastography (TE) and acoustic radiation force impulse (ARFI) elastography before the initiation of treatment and 1 year later. Results Body weight and aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels were significantly decreased at 12 and 24 months after SGLT-2i treatment. The decrease in the levels of ALT at 12 and 24 months was significantly correlated with the level of ALT at the initiation of SGLT-2i (r=0.813, p=0.001 and r=0.867, p=0.0001, respectively). SGLT-2i also reduced the CAP and velocity of shear wave (Vs) values at 12 months (CAP 315.1±43.4 db/mL→293.1±27.2 db/mL, p=0.027; Vs 1.87±0.8 m/s→ 1.48±0.6 m/s, p=0.011). Conclusion SGLT-2i treatment improved the liver function test results and reduced the body weight in NAFLD patients over a period of 12-24 months. This improvement was greater in patients with higher ALT values at baseline than in those with lower values.

Risk Factors and Clinical Course for Liver Steatosis or Nonalcoholic Steatohepatitis After Living Donor Liver Transplantation.

BACKGROUND: Posttransplant liver steatosis occurs frequently and can affect patient outcome. Our aim was to clarify the risk factors for steatosis or steatohepatitis after living donor liver transplantation (LT) through a retrospective examination of recent 100 living donor LT recipients and their liver donors. METHODS: Liver biopsy was performed at 1 year after LT and each year, thereafter, or as needed due to abnormal liver enzyme levels, with a median follow-up of 4 years (2-10 years). RESULTS: Liver steatosis (≥5%) was identified in 33 cases, with steatohepatitis identified in 9 of 33 patients with liver steatosis. Recipients with liver steatosis were younger than those without steatosis (53.4 ± 9.5 years vs 57.6 ± 9.9 years, respectively; P = 0.045). Of note, the prevalence of steatosis was significantly higher among LT recipients who received a graft from a donor with steatosis than without (60% vs 23%, respectively; P = 0.001). Donor steatosis was also associated with steatohepatitis in recipients after LT (steatohepatitis/simple steatosis, 88%:50%). On multivariate analysis, younger recipient age (P = 0.023) and donor steatosis (P = 0.005) were independent risk factors of liver steatosis after LT. Among the 33 recipients in our study group, 26 were assessed by serial liver biopsies, with 6 showing progression of the nonalcoholic fatty liver disease activity score. An increase in body weight was predictive of steatosis progression after LT (P = 0.005). CONCLUSIONS: Age and donor steatosis influence the risk of liver steatosis and steatohepatitis in recipients after LT. The clinical course of steatosis is relatively benign, with only 19% developing nonalcoholic fatty liver disease activity score and 7.6% significant fibrosis.

Serum exosomal microRNA-122 and microRNA-21 as predictive biomarkers in transarterial chemoembolization-treated hepatocellular carcinoma patients.

Exosomal microRNAs (miRNAs) have been investigated as potential novel biomarkers, and miR-122 and miR-21 were shown to be important in hepatocellular carcinoma (HCC). We analyzed the importance of serum exosomal miRNA expression levels in HCC patients that underwent transarterial chemoembolization (TACE). Seventy-five HCC patients who underwent TACE as the initial treatment in Nagasaki University Hospital were enrolled. Exosomal miRNAs were isolated from serum samples collected before and after TACE. Exosomal miR-122 expression levels significantly decreased after TACE (P=0.012), while the exosomal miR-21 expression levels did not significantly change. The expression levels of exosomal miR-122 before TACE were shown to correlate significantly with aspartate aminotransferase (r=0.31, P=0.004) and alanine aminotransferase (r=0.33, P=0.003) levels, tumor diameter (r=0.29, P=0.010) and Child-Pugh score (r=-0.28, P=0.013). The median survival time for all patients was 47 months, and neither of the investigated exosomal miRNAs were shown to be independent factors associated with the disease-specific survival. According to the median relative expression of miR-122 after TACE/before TACE (miR-122 ratio) in liver cirrhosis patients (n=57), the patients with a higher miR-122 ratio had significantly longer disease-specific survival, compared with that of the patients with the lower miR-122 ratio (P=0.0461). Multivariate Cox proportional hazards regression analysis of clinical parameters revealed that a lower exosomal miR-122 ratio (HR 2.720; 95% confidence interval, 1.035-8.022; P=0.042) is associated with the disease-specific survival. Taken together, our results demonstrate that the exosomal miR-122 level alterations may represent a predictive biomarker in HCC patients with liver cirrhosis treated with TACE.

Utilization and efficacy of elbasvir/grazoprevir for treating hepatitis C virus infection after liver transplantation.

AIM: Recently, elbasvir/grazoprevir combination therapy (EBR/GZR) was reported to have excellent antiviral effects for chronic genotype 1 hepatitis C virus (HCV) infection. However, it has not been recommended for patients with post-liver transplant (LT) HCV re-infections because of a lack of evidence for effectiveness and drug-drug interactions. METHODS: We report the usage of EBR/GZR in five post-LT HCV re-infected patients with the kinetics of renal function and tacrolimus trough levels during and after therapy. Furthermore, to evaluate the antiviral effects, we examined the HCV kinetics during and after therapy and compared this with other interferon-free therapy in post-LT patients (n = 19). RESULTS: All patients treated with EBR/GZR therapy obtained rapid virologic response and sustained at 12 weeks post-treatment. There was no evidence of worsening estimated glomerular filtration rates. Three patients were given tacrolimus as immunosuppressive therapy and its trough levels were controllable with dosage adjustments. One patient developed grade 1 diarrhea 3 days after therapy induction. To evaluate the antiviral effects of EBR/GZR therapy for these patients, we compared them to the effects of daclatasvir/asunaprevir combination therapy (n = 8) and sofosbuvir/ledipasvir combination therapy (n = 11). The EBR/GZR combination was not inferior to other therapies in its early phase and late-phase antiviral effects. CONCLUSIONS: Although further studies with a larger number of patients are required, we suggest that EBR/GZR therapy is an alternative therapy for patients with post-LT genotype 1 HCV re-infection.

Ketone bodies as a predictor of prognosis of hepatocellular carcinoma after transcatheter arterial chemoembolization.

OBJECTIVE: Arterial ketone bodies, which reflect liver function, have been investigated. However, the relationship between venous ketone bodies and hepatocellular carcinoma (HCC) is unclear. We investigated whether prognosis of patients with HCC after transcatheter arterial chemoembolization (TACE) was associated with venous blood ketone bodies. METHODS: Sixty-eight patients with HCC who underwent TACE were recruited for this study. The venous blood ketone body levels were measured 1 d before (pretreatment) and 7 d after TACE (posttreatment). Skeletal muscle quality was evaluated using the intramuscular adipose tissue content (IMAC). RESULTS: Of the 68 patients, 43 (63.2%) were male, with median age of 73.0 y, and the IMAC was -0.274 (range -0.82 to 0.24). The median ketone body levels pre- and posttreatment were 63.0 µmol/L (13-310) and 48.0 µmol/L (8-896), respectively. The cumulative survival rate of patients with total ketone body ratio ([TKBR]: posttreatment/pretreatment total ketone bodies) <1 was 86.6%. The rate with TKBR ≥1 was 59.0% at 300 d (P < 0.05). Cox regression analysis identified the TKBR (≥1, hazard ratio: 2.954, 95% confidence interval [CI]: 1.040-8.390, P = 0.030) that independently and significantly predicted the patients' prognoses. Logistic regression analysis revealed the IMAC (>-0.2745, odds ratio: 3.958, 95% CI: 1.137-13.779, P = 0.031) that predicted TKBR. TKBR and IMAC were positively correlated (rS = 0.358, P = 0.003). CONCLUSIONS: The changes in the venous ketone body were associated with the muscle status and predicted the prognosis of patients with HCC who underwent TACE. The venous ketone bodies could be a new predictor of the prognosis of HCC patients after TACE.

Current characteristics of hemophilia patients co-infected with HIV/HCV in Japan.

Over 30 years have passed since co-infection with human immunodeficiency virus (HIV)/hepatitis C virus (HCV) was first documented in hemophilia patients in Japan. In such cases, the leading cause of mortality is reportedly HCV-associated end-stage liver disease. However, the current characteristics of hemophilia patients co-infected with HIV/HCV are unknown. The aim of the present study was to reveal the current characteristics, notably HCV geno-prevalence and liver function, among hemophilia patients co-infected with HIV/HCV in Japan. Current characteristics were evaluated using cross-sectional retrospective data of 44 hemophilia patients positive for anti-HCV and anti-HIV antibodies who underwent screening of liver dysfunction. A total of 56.8% of hemophilia patients co-infected with HIV/HCV were positive for HCV RNA. The most common HCV genotypes were 1a, 1b and 3a. Liver cirrhosis was diagnosed in 26.3% patients negative for HCV RNA and 60.0% patients positive for HCV RNA. Decompensated liver cirrhosis was diagnosed in 33.3% HCV RNA-positive patients and none of the HCV RNA-negative patients. The rate of liver cirrhosis was greater for HCV genotype 3a compared with other genotypes. Overall, the current primary HCV RNA genotypes among hemophilia patients co-infected with HIV/HCV are 1a, 1b and 3a. Over 50% of HIV/HCV co-infected hemophilia patients positive for HCV RNA were diagnosed with liver cirrhosis and some were diagnosed with decompensated liver cirrhosis.

PNPLA3 as a liver steatosis risk factor following living-donor liver transplantation for hepatitis C.

AIM: Liver steatosis frequently occurs following liver transplantation (LT) and can affect patient outcome. Here, we aimed to clarify the steatosis and steatohepatitis risk factors that apply after living-donor LT for chronic hepatitis C. METHODS: We retrospectively examined 43 transplant recipients and donors, and tested for single nucleotide polymorphisms in the PNPLA3 gene. Liver biopsies taken 1 year after transplantation and yearly thereafter, or when abnormal liver enzyme levels were detected, were examined by histopathology. RESULTS: Liver steatosis (>5% steatotic hepatocytes) was evident in 13 of 43 cases (30%), and steatohepatitis in 3 (7.0%). The average time to steatosis after LT was 2.74 ± 1.55 years. The PNPLA3 rs738409 GG genotype, a steatosis risk factor, was identified in 13 recipients and 10 donors. Steatosis prevalence did not differ according to recipient genotype. However, this condition was significantly more common among patients who received tissue from donors carrying the rs738409 GG genotype compared to those with grafts from donors of the CC or CG genotype (60, 7, and 26%, respectively; P < 0.05). All 3 steatohepatitis cases were associated with the GG donor genotype. CONCLUSION: The PNPLA3 rs738409 GG donor genotype affects liver steatosis and steatohepatitis risk following living-donor LT.

Hepatitis C Virus Infection Increases c-Jun N-Terminal Kinase (JNK) Phosphorylation and Accentuates Hepatocyte Lipoapoptosis.

BACKGROUND Hepatitis C virus (HCV) infection and metabolic diseases including nonalcoholic steatohepatitis (NASH) exhibit a complex interplay. Although free fatty acid-mediated apoptosis is a prominent feature of NASH, the impact of HCV infection on hepatocyte lipotoxicity has remained largely unexplored. The study aimed at identifying whether infection by HCV affected the apoptotic pathway in hepatocytes during fatty acid assault. MATERIAL AND METHODS OR6 cells, which are derived from human hepatocellular carcinoma Huh-7 cells and harbor a full-length HCV RNA genome replication system, were treated with palmitate. Apoptosis was examined by 4',6-diamidino-2-phenylindole staining. Activation and expression of JNK, Bim, cIAP-1, and Mcl-1 were examined by immunoblotting. mRNA expression of CHOP, a major player in endoplasmic reticulum stress-mediated apoptosis, was assessed by real-time PCR. RESULTS Palmitate-induced hepatocyte apoptosis was significantly enhanced in OR6 cells compared to cured cells, in which the HCV genome had been eradicated by treatment with interferon-α. Although basal expression of CHOP mRNA was enhanced in OR6 cells compared to cured cells, it was similarly upregulated in both cell lines following palmitate treatment. Notably, palmitate-induced JNK phosphorylation was accentuated in OR6 cells compared to cured cells. Inhibition of JNK with SP600125 attenuated palmitate-induced apoptosis. Palmitate-mediated upregulation of BH3-only protein Bim, which acts downstream of JNK, was also enhanced in OR6 cells compared to cured cells. In contrast, Mcl-1 and cIAP-1 were equally reduced in OR6 cells and cured cells following palmitate treatment. CONCLUSIONS These findings suggest that during lipoapoptosis, HCV infection may enhance hepatocyte toxicity by increasing JNK phosphorylation.

Significance of psoas muscle thickness as an indicator of muscle atrophy in patients with hepatocellular carcinoma treated with sorafenib.

Sarcopenia has been reported to be associated with the prognosis of patients with liver cirrhosis and hepatocellular carcinoma (HCC). The aim of the present study was to determine whether sarcopenia was associated with the prognosis of patients with HCC treated with sorafenib. A total of 40 patients with HCC who were treated with sorafenib were evaluated. As an indicator of skeletal muscle mass, transverse psoas muscle thickness (TPMT) was measured on computed tomography images at the level of the umbilicus prior to treatment initiation and after 1-3 months of treatment. Pre-TPMT/height was not associated with progression-free survival (PFS) or overall survival (OS). The change in TPMT/height prior to and following treatment was also not associated with PFS; however, the change of TPMT/height was an independent factor affecting OS (P=0.020). A total of 40 patients were divided into two groups depending on the degree of TPMT/height loss (mild and severe muscle atrophy groups). Patients with mild muscle atrophy exhibited a significantly longer OS compared with patients with severe muscle atrophy (P=0.045). Thus, the change in skeletal muscle thickness calculated as TPMT/height may be a simple predictor of survival for patients with HCC treated with sorafenib.

Genome-wide association studies identify PRKCB as a novel genetic susceptibility locus for primary biliary cholangitis in the Japanese population.

A previous genome-wide association study (GWAS) performed in 963 Japanese individuals (487 primary biliary cholangitis [PBC] cases and 476 healthy controls) identified TNFSF15 (rs4979462) and POU2AF1 (rs4938534) as strong susceptibility loci for PBC. In this study, we performed GWAS in additional 1,923 Japanese individuals (894 PBC cases and 1,029 healthy controls), and combined the results with the previous data. This GWAS, together with a subsequent replication study in an independent set of 7,024 Japanese individuals (512 PBC cases and 6,512 healthy controls), identified PRKCB (rs7404928) as a novel susceptibility locus for PBC (odds ratio [OR] = 1.26, P = 4.13 × 10-9). Furthermore, a primary functional variant of PRKCB (rs35015313) was identified by genotype imputation using a phased panel of 1,070 Japanese individuals from a prospective, general population cohort study and subsequent in vitro functional analyses. These results may lead to improved understanding of the disease pathways involved in PBC, forming a basis for prevention of PBC and development of novel therapeutics.

Glucose fluctuations reduce quality of sleep and of life in patients with liver cirrhosis.

BACKGROUND: Sleep disturbance and decreased health-related quality of life (HRQOL) are significant complaints in patients with liver cirrhosis. Although the etiology of these complications is unclear, we propose that glucose intolerance may be a predisposing factor. Therefore, our aim was to investigate the relationship between glucose intolerance and these complications. METHODS: We assessed continuous glucose monitoring in 43 patients with chronic liver disease. Among these patients, 36 completed the Pittsburgh Sleep Quality Index (PSQI), the 36-Item Short-form Health Survey (SF-36), and the Neuropsychological Test (NPT). We also assessed the change in glucose fluctuations between preoperative periods and 1 year after liver transplantation in 13 patients. RESULTS: Standard deviation (SD) of blood glucose was 24.15 ± 13.52. SD values correlated to glucose metabolism measures, including HbA1c and glycoalbumin. SD values also correlated to markers of liver fibrosis, including type IV collagen. Twenty-one patients (58.3 %) were classified as "poor" sleepers, with a global PSQI score ≥6. Glucose fluctuations correlated with the global PSQI score (r = 0.456, p = 0.008) and the SF-36 score (r = 0.434, p = 0.013). Multivariate regression analysis identified SD values as an independent risk factor for sleep disturbance (r = 0.12, p = 0.039) and decreased HRQOL (r = -0.32, p = 0.024). SD values did not correlate with the NPT. SD values were also improved in 11 (84.6 %) patients 1 year after liver transplantation. CONCLUSION: Abnormal glucose fluctuations are a risk factor for sleep disturbance and decrease of HRQOL in patients with cirrhosis.

Prevalence of Restless Legs Syndrome in Patients with Inflammatory Bowel Disease.

BACKGROUND AND AIM: There has been increased interest in sleep disorders in patients with inflammatory bowel disease (IBD). Studies in North America and Europe reported that the prevalence of restless legs syndrome (RLS) is much higher in patients with Crohn's disease (CD) than in the general population. The aim of this study was to reveal the prevalence and clinical features of RLS in Japanese patients with IBD and investigate the influence of RLS on sleep quality and quality of life (QOL). METHODS: The study included 80 outpatients with IBD who visited Nagasaki University Hospital between December 2012 and July 2014. All patients completed the international RLS study group rating scale, a validated measure of the presence of RLS. Sleep quality was assessed using the Japanese version of the Pittsburgh Sleep Quality Index (PSQI), and health-related QOL was assessed using the Japanese version of the 36-item short form healthy profile (SF-36) version 2. RESULTS: The prevalence of RLS in patients with IBD was 20%, including rates of 21.7% in patients with ulcerative colitis (UC) and 17.6% in patients with CD. Among patients with CD, the proportion of women and serum level of CRP were higher in the RLS group than in the non-RLS group. Among those with UC, there were no differences in clinical characteristics between the RLS and non-RLS groups. Patients in the RLS group slept significantly less well than those in the non-RLS group (PSQI > 5; 62.5 vs. 34.4%, P < 0.05). No significant relationships were observed between QOL indices and the presence of RLS (SF-36 physical score, 46.8 vs. 50.1; mental score, 43.8 vs. 45.7; role/social score, 48.1 vs. 49.2). CONCLUSIONS: RLS occurs frequently in Japanese patients with UC as well as CD. RLS affects sleep quality but not QOL, and it should be considered one of the causes of sleep disturbance in patients with IBD.

Elevated Fasting Plasma Glucose before Liver Transplantation is Associated with Lower Post-Transplant Survival.

BACKGROUND The risk of liver cirrhosis is higher among individuals with diabetes mellitus, and a cirrhotic patient with diabetes may have a poorer prognosis after liver transplantation compared to a patient without diabetes. Thus, we evaluated whether fasting plasma glucose prior to receiving a liver transplant was a prognostic factor for post-transplant survival. MATERIAL AND METHODS Ninety-one patients received a living donor liver transplant between November 2005 and December 2012. Patients were considered diabetic if they were prescribed diabetes medications or had impaired glucose tolerance as measured by an oral glucose tolerance test. Each patient was monitored through December 31, 2013, to evaluate prognosis. RESULTS Fasting plasma glucose of at least 100 mg/dL significantly decreased survival following transplant (52% in the high FPG group compared to 78% in the control group, p=0.04), while postprandial hyperglycemia had no effect on survival. Additionally, overall mortality and the incidence of vascular disease were significantly higher among patients with uncontrolled plasma glucose. Impaired fasting plasma glucose was significantly and inversely associated with overall survival in the univariate and multivariate analyses, while creatinine (at least 1 mg/dL) was inversely associated with survival in the univariate analysis. CONCLUSIONS Elevated fasting plasma glucose prior to liver transplantation was inversely associated with post-transplant survival. This effect may be due to underlying microangiopathy as a result of uncontrolled diabetes before transplantation. Our data demonstrated the importance of controlled blood glucose prior to liver transplantation.

Risk factors for osteoporosis in patients with end-stage liver disease.

Patients with end-stage liver disease (ESLD) were evaluated and their clinical features were compared with the aim of identifying risk factors for osteoporosis. Seventy-nine patients with ESLD were enrolled in the current study. Bone mineral density (BMD) was assessed by dual-energy X-ray absorptiometry and compared with clinical features in patients with ESLD. BMD was identified to be significantly correlated with body mass index (r=0.430; P=0.001) and inversely correlated with total bile acid (r=-0.228; P=0.049) and urine N-telopeptide type I collagen/creatinine ratio (r=-0.280; P=0.024). Patients with osteoporosis were significantly older (osteoporosis vs. no osteoporosis, 63.0 vs. 56.0 years; P<0.05) and had higher values for total bile acid (osteoporosis vs. no osteoporosis, 306.0 vs. 129.1 µmol/l; P<0.05) and corrected calcium [osteoporosis vs. no osteoporosis, 9.85 (8.7-10.7) vs. 9.70 (8.8-10.6) mg/dl; P<0.05]. In multivariate analysis, age (ß=-0.015±0.06; P=0.009) and total bile acid (ß=-0.001±0.0001; P=0.041) were identified as independent factors for osteoporosis. Finally, the risk score for osteoporosis was defined as follows: Risk score=1.78-0.001 × total bile acid-(0.16 × age). The area under the receiver operating characteristic (ROC) curve risk score for osteoporosis is 0.778. Thus, the risk scores calculated in the present study may be used to predict osteoporosis in patients with ESLD.